Journal of Medical Genetics最新文献

{"title":"Calibration and refinement of ACMG/AMP criteria for variant classification with BayesQuantify.","authors":"Sihan Liu, Xiaoshu Feng, Yang Wu, Fengxiao Bu","doi":"10.1136/jmg-2025-110863","DOIUrl":"10.1136/jmg-2025-110863","url":null,"abstract":"<p><strong>Background: </strong>Improving the precision and accuracy of variant classification in clinical genetic testing requires further specification and stratification of the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) criteria. While the ClinGen Bayesian framework enables quantitative evidence calibration for selected criteria, standardised tools to optimise evidence thresholds and refine ACMG/AMP criteria remain underdeveloped.</p><p><strong>Methods: </strong>To address this need, we developed <i>BayesQuantify</i>, an R package that provides a unified tool for quantifying evidence strength for the ACMG/AMP criteria based on the Bayesian framework. <i>BayesQuantify</i> accepts a variant classification file as input and automatically calculates the odds of pathogenicity for each evidence strength, incorporating a user-provided prior probability of pathogenicity. Through bootstrapping, <i>BayesQuantify</i> generates thresholds by aligning the 95% lower bound of positive likelihood ratio/local positive likelihood ratio with the odds of pathogenicity for different evidence strengths. Three independent datasets derived from ClinVar, HGMD and gnomAD were used to evaluate the utility of <i>BayesQuantify</i>.</p><p><strong>Results: </strong><i>BayesQuantify</i> supports the calibration of both categorical and continuous ACMG/AMP evidence. Specifically, we replicated the PP3/BP4 thresholds for four computational tools recommended by ClinGen. Our analysis also indicated that the PM2 criterion can reach 'supporting,' or 'moderate,' evidence, varying by prior probability. Importantly, we established thresholds for supporting, moderate and strong evidence for in-silico tools, thereby expanding the application of PP3/BP4 criteria for missense variants in the <i>PTEN</i> gene.</p><p><strong>Conclusion: </strong><i>BayesQuantify</i> is a user-friendly tool that enhances the flexibility and reproducibility of ACMG/AMP criteria refinement, thus improving the accuracy and consistency of variant classification. The package is freely available at https://github.com/liusihan/BayesQuantify.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the unique characteristics of genes with dual autosomal dominant and recessive inheritance: mechanisms, phenotypes and candidate identification.","authors":"Shlomit Ezer, Tal Sido, Jonathan Rips, Ronit Hoffman Lipschuetz, Adina Fuchs, Bassam Abu-Libdeh, Elena Chervinsky, Nadirah S Damseh, Nada Danial-Farran, Ilham Morani, Ann Saada, Mohammed Al-Raqad, Somaya Salah, Shira Yanovsky-Dagan, Nadra Samra, Hanna Mandel, Stavit A Shalev, Hagar Mor-Shaked, Joël Zlotogora, Tamar Harel","doi":"10.1136/jmg-2025-110872","DOIUrl":"10.1136/jmg-2025-110872","url":null,"abstract":"<p><strong>Background: </strong>Autosomal dominant (AD) inheritance often arises through haploinsufficiency, dominant-negative or gain of function (GoF) effects, while autosomal recessive (AR) inheritance generally results from partial or complete loss of function (LoF). Yet, a subset of genes demonstrates both inheritance patterns. We aimed to curate a list of such 'AD/AR' genes and to propose additional candidates.</p><p><strong>Methods: </strong>AD/AR genes were subcategorised based on genotype-phenotype correlations and disease mechanisms. Using bioinformatic analyses, we compared genes with AD, AR and AD/AR inheritance across various metrics, including gnomAD constraint values, exon count, protein length, quaternary structure and gene ontology terms. A machine learning-based metric was used to account for interdependence among features.</p><p><strong>Results: </strong>Pathogenic variants in AD/AR genes can lead to distinct or similar phenotypes, depending on the molecular mechanism. AD/AR genes exhibit unique bioinformatic properties such as intermediate constraint scores, a combination of gene ontology terms, a greater average number of exons and an elevated propensity to form homomeric/heteromeric proteins. We identified homozygous LoF or clinically reported variants in nine genes previously classified as AD only.</p><p><strong>Conclusion: </strong>Collectively, the data suggest that AD/AR genes possess distinctive features that likely underpin their dual inheritance modes. We propose nine candidate AD/AR genes and emphasise caution in filtering by inheritance type alone.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health-related quality of life in patients with mitochondrial disease and their carers.","authors":"Deborah Schofield, Joshua Kraindler, Katherine Lim, Owen Tan, Sameen Haque, Karen Crawley, Sarah West, Adam Percival, Jayamala Parmar, Rupendra Shrestha, Carolyn Sue","doi":"10.1136/jmg-2025-110896","DOIUrl":"https://doi.org/10.1136/jmg-2025-110896","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial diseases are a group of rare, chronic disorders with a significant disease burden; however, there is limited knowledge about their effects on the health-related quality of life (HRQoL) of patients and their carers. This study estimates HRQoL among adult patients with mitochondrial diseases and their carers, using the Assessment of Quality-of-Life 8D (AQoL-8D), a validated instrument for measuring health utilities.</p><p><strong>Methods: </strong>Ninety-nine adult patients and 24 carers were recruited to the Economic and Psychosocial Impacts of Caring for Families Affected by Mitochondrial Disease (EPIC-MITO) Study, based in New South Wales, Australia.</p><p><strong>Results: </strong>Adult patients exhibited significantly lower utility values (0.52) compared with age-adjusted and gender-adjusted population norms (0.80; p<0.001). Regression analysis shows that mental health disorders, sleep disorders, financial stress and female gender were associated with reduced HRQoL. Carers also demonstrated AQoL-8D utility values (0.70) significantly below age-adjusted and gender-adjusted population norms (0.81; p=0.01) reflecting the broader burden of mitochondrial diseases on families.</p><p><strong>Conclusion: </strong>With increasing use of genetic testing and genomic sequencing, as well as hope for gene therapies, health utility values will be necessary for economic evaluations of new interventions for mitochondrial disease. This paper shows the substantial impact on HRQoL of mitochondrial disease measured through utilities. The utility values from this paper can inform future economic evaluations for interventions for patients with mitochondrial disease. Further, the paper demonstrated that mitochondrial disease not only reduces the HRQoL of patients but also impacts the HRQoL of carers.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sephardic origins revealed for rare skin disorder, recessive dystrophic epidermolysis bullosa, in individuals carrying the unique c.6527insC mutation.","authors":"Emily Mira Warshauer, Paul A Maier, Goran Runfeldt, Ignacia Fuentes, Maria José Escamez, Laura Valinotto, Monica Natale, Graciela Manzur, Nuria Illera, Marta Garcia, Marcela Del Rio, Angeles Mencia, Almudena Holguin, Fernando Larcher, Garrett Hellenthal, Adam R Brown, Liliana Consuegra, Carolina Rivera, Inês Nogueiro, Jean Tang, Anthony Oro, Peter Marinkovich, Francis Palisson, Matthias Titeux, Alain A Hovnanian, Eli Sprecher, Karl Skorecki, David Norris, Anna Bruckner, Igor Kogut, Ganna Bilousova, Dennis Roop","doi":"10.1136/jmg-2025-110967","DOIUrl":"https://doi.org/10.1136/jmg-2025-110967","url":null,"abstract":"<p><strong>Background: </strong>Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and severe blistering skin disorder caused by loss-of-function mutations in the type VII collagen gene (<i>COL7A1</i>). The <i>COL7A1</i> c.6527insC mutation is curiously prevalent among individuals with RDEB and is found worldwide in Europe and the Americas. Previous research has suggested the possibility of a Sephardic Jewish origin of the mutation; however, individuals with RDEB are not known to have predominant Jewish ancestry.</p><p><strong>Methods: </strong>In this study, a global cohort of individuals with RDEB with the c.6527insC founder mutation from Spain, France, Argentina, Chile, Colombia and the USA were investigated by autosomal genotyping, pairwise identical-by-descent matching and a local ancestry analysis. Age estimation analysis was performed to determine when Jewish founders introduced the c.6527insC mutation into Iberian and Native American populations (~900 CE and 1492 CE, respectively).</p><p><strong>Results: </strong>Sephardic ancestry was identified at the haplotype spanning the c.6527insC mutation in 85% of the individuals, despite mixed ancestry elsewhere in the genome and no known recent Sephardic ancestry. Identical-by-descent matching between this RDEB subpopulation and a known crypto-Jewish community in Belmonte, Portugal was also ascertained, providing support for crypto-Jewish ancestry in this RDEB subpopulation.</p><p><strong>Conclusion: </strong>The identification of this unique RDEB subpopulation unified by the single most prevalent c.6527insC mutation holds great potential to facilitate promising new RDEB therapies using CRISPR Cas 9 gene and base editing. The identification of a single guide RNA allowing efficient and safe editing of this variant would represent a unique drug to treat a large cohort of patients with the same founder mutation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Six at Sixty. 'No gain, no pain': medical genetics taking Nav1.7 from target to pharmacy.","authors":"Pu Xia, Ran Mo, Linghan Hu, Yong Yang","doi":"10.1136/jmg-2025-111174","DOIUrl":"10.1136/jmg-2025-111174","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"654-657"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"'Knowing and Treating Kosaki/Penttinen syndrome' international collaborative consortium: recommendations for follow-up, natural history and a real-life observational study about safety and efficacy profile of tyrosine kinase inhibitors.","authors":"Yordi-Michaël Bouhatous, Cecilie Bredrup, Agnes Maurer, Liubinka Mirakovska, Alison Foster, Kenjiro Kosaki, Céline Jost, Jean-Baptiste Demoulin, Maxime Luu, Pierre Vabres, Jean-Emmanuel Kurtz, Elise Schaefer, Anne Guimier, Valerie Cormier-Daire, Derek Lim, Sarah Thompson, Lorin Olson, Hae Ryong Kwon, Cristina Aguirre-Rodriguez, Unai Hernandez-Dorronsoro, Itziar Martinez-Soroa, Helena Iznardo, José-Manuel Mascaró, Eulalia Baselga, Silvia Kalantari, Alessandro Mussa, Andrea Gazzin, Diana Carli, Ingrid Svinvik, Hatice Mutlu-Albayrak, Sarah Bluefeather, Yuri Zarate, Toshiki Takenouchi, Thirona Naicker, Antoinette Chateau, Ashmika Gokhul, Anele Dube-Pule, Muzhirah Haniffa, Winnie Ong Peitee, Ann Nordgren, Maud Carpentier, Christine Binquet, Anne-Sophie Briffaut, Laurence Bal, Dinel Pond, Cecilie F Rustad, Marc Bardou, Laurence Faivre","doi":"10.1136/jmg-2024-110600","DOIUrl":"10.1136/jmg-2024-110600","url":null,"abstract":"<p><strong>Background: </strong>5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in <i>PDGFRB</i>. Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future. The bi-annual remote meetings provide an opportunity to share knowledge on these syndromes.</p><p><strong>Material and methods: </strong>The consortium has validated the communication process, standardised follow-up guidelines, established a database to improve the natural history of these syndromes and evaluated the real-world safety and efficacy profile of TKIs by comparing treated and untreated patients. The regulatory framework is in place.</p><p><strong>Results: </strong>As of November 2024, 18 teams in 13 countries have joined the consortium. More than 25 patients have been identified worldwide, either published or unpublished; 7 of them were treated with a TKI. The guidelines include retrospective and prospective sections for each organ affected by the disease and are based on literature and expert opinion. They also include recommendations to standardise the assessment of the efficacy and safety of treatments prescribed under compassionate use.</p><p><strong>Conclusion: </strong>The consortium welcomes new teams on an ongoing basis. Recommendations are especially useful in such ultra-rare degenerative diseases. The real-life observational study seems to be an appropriate model to improve knowledge, including the assessment of treatment efficacy when the prevalence of the disease does not allow the setting up of clinical trials.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"656-663"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reproductive decision-making and pregnancy in germline <i>CDH1</i> variant carriers.","authors":"Amber Famiglietti Gallanis, Cassidy Bowden, Rachael Lopez, Jessica Turner, Grace-Ann Fasaye, Shruthi Reddy Perati, Jonathan M Hernandez, Andrew Blakely, Jeremy L Davis","doi":"10.1136/jmg-2025-110857","DOIUrl":"10.1136/jmg-2025-110857","url":null,"abstract":"<p><strong>Background: </strong>Diagnosis of a hereditary cancer syndrome may impact family planning, particularly in reproductive age individuals. Factors influencing reproductive decision-making are understudied in individuals with germline <i>CDH1</i> pathogenic or likely pathogenic (P/LP) variants.</p><p><strong>Methods: </strong>We characterised reproductive decision-making and perinatal outcomes in 121 individuals aged 18-49 with hereditary diffuse gastric and lobular breast cancer syndrome due to a germline <i>CDH1</i> P/LP variant.</p><p><strong>Results: </strong>Half of individuals (50%, 60/121) reported their <i>CDH1</i> diagnosis impacted family planning. Psychosocial and economic barriers to reproduction were encountered by 47% (56/119) of patients. Additionally, 12% (15/121) of individuals delayed pregnancy to prioritise personal cancer risk management with either endoscopic surveillance, prophylactic total gastrectomy (PTG) or mastectomy. Women were more likely to experience guilt about passing their <i>CDH1</i> variant to offspring compared with men. Perinatal and fetal outcomes were investigated in six women who gave birth at a median time of 24 months (IQR 20-44) after PTG. Maternal micronutrient deficiencies were not uncommon in pregnant women after PTG despite compliance with a bariatric, prenatal multivitamin. Majority of women who became pregnant after PTG reported worsening post-gastrectomy syndromes. Most infants (90%, 9/10) born after PTG were full-term and no fetal complications were reported.</p><p><strong>Conclusion: </strong>Reproductive decision-making is complex in individuals with germline <i>CDH1</i> variants, who often encounter psychosocial and physical challenges during family planning and pregnancy. However, successful pregnancy is possible after PTG with the guidance of a multidisciplinary team including maternal fetal medicine specialists and a registered dietitian.</p><p><strong>Trial registration number: </strong>NCT03030404.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"609-616"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-read DNA and RNA sequencing for inherited polyposis and colorectal cancer: cryptic intronic variants and multiple mutational mechanisms.","authors":"Angela L Jacobson, Amal AbuRayyan, Suleyman Gulsuner, Haley Slater, Yagiz Anasiz, Sirajummuneer M Ahmad, Ming K Lee, Jessica Mandell, Emily J Rettner, Eric Q Konnick, Colin Pritchard, Mary-Claire King, Tom Walsh, Brian H Shirts","doi":"10.1136/jmg-2025-110851","DOIUrl":"10.1136/jmg-2025-110851","url":null,"abstract":"<p><strong>Background: </strong>Molecular genetic diagnoses are critical to prevention and treatment of inherited polyposis and colorectal cancer. 19 genes responsible for these conditions are known, but many severely affected patients and families remain unsolved. Cryptic intronic variants that alter splicing of these genes and incomplete characterisation of recessive predisposition contribute to these diagnostic gaps.</p><p><strong>Methods: </strong>Adaptive sampling long-read DNA sequencing targeted to 19 colon cancer genes, paired with direct long-read RNA whole-transcriptome sequencing, was undertaken for four patients referred for deficiency of mismatch repair proteins and/or familial polyposis, for whom multigene panel testing yielded negative or uncertain germline results.</p><p><strong>Results: </strong>Genetic diagnoses were obtained for all four patients. Each patient carried a cryptic intronic germline variant in a different colon cancer gene. The variants abrogated splicing by various mechanisms, all leading to loss of gene function. Patient 1 was heterozygous for intronic insertion into <i>MSH2</i> of an Alu element, leading to extension of transcription into the affected intron and a stop. Patient 2 was heterozygous for deep intronic insertion into <i>APC</i> of a Long Interspersed Nuclear Element (LINE), creating a pseudoexon and a stop. Patient 3 was compound heterozygous at <i>MLH3</i>, including a cryptic intronic substitution leading to exon skipping and a stop. Patient 4 was compound heterozygous at <i>MUTYH</i>, including a deep intronic deletion yielding an extremely short intron and transcriptional loss of an exon encoding a critical protein domain.</p><p><strong>Conclusion: </strong>Paired long-read DNA and RNA sequencing can enhance diagnostic yield through detection of cryptic intronic variants that impact cancer predisposition.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"617-623"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12318545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the use of a patient-facing digital app to support Lynch syndrome carriers in the management of their condition.","authors":"Megan I Hopkinson, Reena Sooch, Charlotte Beauvais, Shirley V Hodgson, Tracy Ann Smith, Madonna Jonhera, Stan Shepherd, Julian Barwell","doi":"10.1136/jmg-2025-110710","DOIUrl":"10.1136/jmg-2025-110710","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"628-630"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of whole-body MRI for cancer early detection in Li-Fraumeni syndrome.","authors":"Peter Sodde, Zerin Hyder, Sarah Pugh, Fiona Lalloo, Richard Martin, Calvin Soh, Jawad Naqvi, Richard Whitehouse, D Gareth Evans, Emma Roisin Woodward","doi":"10.1136/jmg-2025-110704","DOIUrl":"10.1136/jmg-2025-110704","url":null,"abstract":"<p><p>Li-Fraumeni syndrome (LFS) is a high-risk hereditary cancer predisposition syndrome affecting 1 in 5000 individuals. Current standard of care in adults includes annual whole-body MRI (WB-MRI) and MRI brain (MRB) surveillance to enable early cancer detection. We performed a retrospective single-centre study of adults with <i>TP53</i> pathogenic germline variants or proven somatic mosaicism undergoing annual WB-MRI surveillance between January 2012 and January 2024, and MRB surveillance between August 2017 and January 2024. 325 WB-MRI scans were performed in 75 individuals. 17 cancers were diagnosed in 16 individuals. Nine out of 17 cancers were WB-MRI detected (7/9 had stage 1/2 disease). Benign incidental findings were identified in 89/325 (27.4%) of WB-MRI scans, prompting 53 additional investigations. As a stand-alone surveillance tool, WB-MRI demonstrated a pan-cohort specificity of 95.5%, negative predictive value of 97.4% and sensitivity of 42.9%. 32 individuals underwent 53 MRB scans detecting one cancer. We report the findings from the longest and largest single-centre experience of WB-MRI surveillance for cancer early detection in adults with LFS, demonstrating a high and acceptable level of cancer exclusion but modest sensitivity with WB-MRI prompting a significant number of additional investigations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"624-627"},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}